Patent NZ-601730-A (NZ)
Title: Prolyl hydroxylase inhibitors and methods of use
Inventor: KAWAMOTO RICHARD MASARU
IPC: A61P7/06
Filed: 2007-06-26
Abstract: 601730 Disclosed are { [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} -acetic acid derivatives as represented by the general formula, as inhibitors of human protein prolyl hydroxylase for stimulating an angiogenic response for increasing blood flow, oxygen delivery and energy utilization in ischemic tissues; wherein R and R1 are each independently: i) hydrogen; ii) substituted or unsubstituted phenyl; or iii) substituted or unsubstituted heteroaryl; provided that R and R1 are not both hydrogen; R2 is OR6 or NR7aR7b; R6 is hydrogen or linear, branched, or cyclic alkyl; R7a and R7b are each independently: hydrogen, linear, branched, or cyclic alkyl; or R7a and R7b can be taken together to form a ring having from 3 to 7 atoms; R3 is hydrogen, methyl, or ethyl; L is an C1-C3 optionally substituted alkylene moiety; R9 is hydrogen or methyl; or a pharmaceutically acceptable salt thereof; and wherein the remaining substituents are as defined herein. Representative compounds include { [5-(4-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid methyl ester, [(3-hydroxy-5-(4-methylphenyl)pyridine-2-carbonyl)amino]acetic acid methyl ester, { [3-hydroxy-5-(3-trifluoromethylphenyl)-pyridine-2-carbonyl]amino} acetic acid methyl ester, [(3-hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)amino]acetic acid methyl ester, ({ 5-[3-(cyclopropanecarbonylamino)phenyl]-3-hydroxypyridine-2-carbonyl} amino)acetic acid methyl ester, 5-(3-chlorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxypyridin-2-yl amide, 5-(3-chlorophenyl)-N-(2-isopropylamino-2-oxoethyl)-3-hydroxypyridin-2-yl amide, 2-{ [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} -2-methyl-propionic acid methyl ester and 5-(3-chlorophenyl)-N-(2-methylamino-2-oxo-1,1-dimethylethyl)-3-hydroxylpyridin-2-yl amide. Further disclosed is a composition comprising one or more compounds as defined above, or a pharmaceutically acceptable salt thereof; and one or more excipients or carriers; for treating a disease selected from diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget’s disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme’s disease, systemic lupus erythematosis, retinopathy of prematurity, Eales’ disease, Behcet’s disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best’s disease, myopia, optic pits, Stargardt’s disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, trauma post-laser complications, diseases associated with rubeosis, and proliferative vitroeretinopathy, Crohn’s disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, solid or blood borne tumors, acquired immune deficiency syndrome, skeletal muscle and myocardial ischemia, stroke, coronary artery disease, peripheral vascular disease, and coronary artery disease.